Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of antagonistic chromatin marks.

Animals Animals, Genetically Modified Centromere / ultrastructure Chromatin / chemistry Chromatin Immunoprecipitation Computational Biology / methods DNA Methylation DNA Transposable Elements Drosophila melanogaster Epigenesis, Genetic Histones / chemistry Humans Imaginal Discs / metabolism Lysine / chemistry Methionine / chemistry Mice Microscopy, Electron, Scanning Microscopy, Fluorescence Mutation Phenotype RNA-Seq
Drosophila H3K27me3 H3K36me2 K27M K36M ash1 krimp oncohistones piRNA transposons

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
02 12 2021
Historique:
received: 01 03 2021
revised: 10 08 2021
accepted: 12 10 2021
pubmed: 6 11 2021
medline: 8 1 2022
entrez: 5 11 2021
Statut: ppublish

Résumé

Histone H3.3 lysine-to-methionine substitutions K27M and K36M impair the deposition of opposing chromatin marks, H3K27me3/me2 and H3K36me3/me2. We show that these mutations induce hypotrophic and disorganized eyes in Drosophila eye primordia. Restriction of H3K27me3 spread in H3.3K27M and its redistribution in H3.3K36M result in transcriptional deregulation of PRC2-targeted eye development and of piRNA biogenesis genes, including krimp. Notably, both mutants promote redistribution of H3K36me2 away from repetitive regions into active genes, which associate with retrotransposon de-repression in eye discs. Aberrant expression of krimp represses LINE retrotransposons but does not contribute to the eye phenotype. Depletion of H3K36me2 methyltransferase ash1 in H3.3K27M, and of PRC2 component E(z) in H3.3K36M, restores the expression of eye developmental genes and normal eye growth, showing that redistribution of antagonistic marks contributes to K-to-M pathogenesis. Our results implicate a novel function for H3K36me2 and showcase convergent downstream effects of oncohistones that target opposing epigenetic marks.

Identifiants

DOI: 10.1016/j.molcel.2021.10.008 PMID: 34739871 PMC: PMC9990445
pubmed: 34739871
pii: S1097-2765(21)00837-6
doi: 10.1016/j.molcel.2021.10.008
pmc: PMC9990445
mid: NIHMS1872924
pii:
doi:

Substances chimiques

Chromatin 0
DNA Transposable Elements 0
Histones 0
Methionine AE28F7PNPL
Lysine K3Z4F929H6

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

4876-4890.e7

Subventions

Organisme : NIH HHS
ID : P40 OD018537
Pays : United States
Organisme : CIHR
ID : MOP-44050
Pays : Canada
Organisme : CIHR
ID : IOP-107945
Pays : Canada
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : CIHR
ID : PJT-156086
Pays : Canada
Organisme : CIHR
ID : FDN-154307
Pays : Canada
Organisme : CIHR
ID : MOP-286756
Pays : Canada

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Amel Chaouch (A)

Department of Biology, McGill University, Montreal, QC, Canada.

Johannes Berlandi (J)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Carol C L Chen (CCL)

Department of Human Genetics, McGill University, Montreal, QC, Canada.

Felice Frey (F)

Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

Shireen Badini (S)

Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

Ashot S Harutyunyan (AS)

Department of Human Genetics, McGill University, Montreal, QC, Canada.

Xiao Chen (X)

Department of Genetics and Development, Columbia University, New York, NY, USA.

Brian Krug (B)

Department of Human Genetics, McGill University, Montreal, QC, Canada.

Steven Hébert (S)

The Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.

Astrid Jeibmann (A)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Chao Lu (C)

Department of Genetics and Development, Columbia University, New York, NY, USA.

Claudia L Kleinman (CL)

Department of Human Genetics, McGill University, Montreal, QC, Canada; The Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.

Martin Hasselblatt (M)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Paul Lasko (P)

Department of Biology, McGill University, Montreal, QC, Canada; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address: paul.lasko@mcgill.ca.

Margret Shirinian (M)

Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon. Electronic address: ms241@aub.edu.lb.

Nada Jabado (N)

Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Paediatrics, McGill University and the Research Institute of the McGill University Health Center, Montreal, QC, Canada. Electronic address: nada.jabado@mcgill.ca.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Stades d'organismes › Organismes génétiquement modifiés › Animal génétiquement modifié › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Centromère › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Techniques d'investigation › Techniques immunologiques › Immunoprécipitation › Immunoprécipitation de la chromatine › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Sciences de l'information › Informatique › Biologie informatique › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées dispersées › Éléments transposables d'ADN › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Eucaryotes › Animaux › Invertébrés › Arthropodes › Insectes › Pterygota › Neoptera › Holometabola › Diptera › Drosophilidae › Drosophila › Drosophila melanogaster › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Structures anatomiques de l'animal › Disques imaginaux › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés essentiels › Lysine › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés soufrés › Méthionine › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Techniques d'investigation › Microscopie électronique › Microscopie électronique à balayage › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Techniques d'investigation › Microscopie de fluorescence › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Histone H3.3 K27M and K36M mutations...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › RNA-Seq › Histone H3.3 K27M and K36M mutations...